Fusidic acid derivatives

Details Fusidic acid derivatives Fusidic acid derivatives

2002-03-07

2004-01-06

Qazi, Sabiha (Department: 1616)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C552S525000, C552S523000, C552S530000, C552S531000

Reexamination Certificate

active

06673783

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel fusidic acid derivatives, to salts and to easily hydrolysable esters thereof, to the preparation of these compounds, to pharmaceutical compositions containing the compounds and to the use of such compounds in medicine. In particular, these compounds exhibit antimicrobial activity and are therefore useful in the treatment of infectious diseases. The compounds of the present invention can be used both in systemic treatment of infections and in topical treatment of infections related to skin and eyes.
BACKGROUND OF THE INVENTION
The antibacterial properties of fusidic acid are well known. It is also known that structural variations may cause significant or total loss of such activity (cf. Godtfredsen et al,
J. Med. Chem.,
Vol. 9, p. 15-22, 1966). It has until now been generally accepted that the double bond between the carbon atoms C-17 and C-20 which connect the side-chain to the tetracyclic ring system is essential for any antibacterial activity (cf. Bodley and Godtfredsen,
Biochem. Biophys. Res. Commun.
46, 1972, pp. 871-877). Reduction of the double bond between C-24 and C-25 of fusidic acid to a single bond resulted in a marginal effect on the antibacterial activity of the molecule whereas additional reduction of the double bond between C-17 and C-20 yielding tetrahydrofusidic acid caused almost complete loss of activity (cf. von Daehne et al.,
Adv. Appl. Microbiol.,
25, p. 95-146,1979, and references cited therein).
SUMMARY OF THE INVENTION
The object of the present invention is to provide semisynthetic analogues of fusidic acid having antimicrobial activity. Said object is achieved with the compounds of the present invention that belong to a class of fusidic acid derivatives in which the side chain is connected to the tetracyclic ring system at C-17 via a fused cyclopropane ring and which in vitro show high antimicrobial activity and favourable stability and pharmacokinetic properties, whereby the compounds of the invention may be used in treatment of infections in humans and animals.
The present invention relates to compounds of the general formula I
wherein
Q
1
, Q
2
and Q
3
are the same or different and independently represent a —(CO)— group; a —(CHOH)— group; a —(CHOR)— group; a —(CHSH)— group; a —(NH)— group; a —(CHNH
2
)— group; a —(C—X)— group, wherein X represents halogen; or a —(CHNHR)— group, wherein R represents an alkyl radical having 1 to 4 carbon atoms or an acyl radical having 1 to 4 carbon atoms; and wherein Q
2
and Q
3
may also independently represent a —(CH
2
)— group;
Y represents hydrogen, hydroxy, an alkyl radical having 1 to 4 carbon atoms, or an acyl radical having 1 to 4 carbon atoms;
A represents an oxygen or a sulphur atom;
R
1
represents an alkyl radical having 1 to 4 carbon atoms, an olefinic group having 2 to 4 carbon atoms, a (C
1
-C
6
) acyl group, (C
3
-C
7
)cycloalkylcarbonyl group or a benzoyl group R
1
being optionally substituted with one or more halogen at azido groups;
and pharmaceutically acceptable salts and easily hydrolysable esters thereof.
In formula I and subsequent formulas herein the dotted lines between C-1 and C-2 and between C-24 and C-25 indicate that the atoms in question are connected with either a double bond or a single bond.
It has surprisingly been found that compounds of formula I exhibit an excellent chemical stability relative to fusidic acid and derivatives thereof which have a carbon-carbon double bond between C-17 and C-20. The superior stability may be due to the absence of Conjugation of the carboxylic acid with a carbon-carbon double bond. The presence of a cyclopropane ring in this position is therefore expected to impart to the present fusidic acid derivatives an improved stability in the presence of light and in solution. As the compounds of formula I are more lipophilic than fusidic acid, they may exhibit an improved absorption profile in lipophilic tissue such as skin, and may therefore be particularly advantageous for incorporation into used in topical formulations for application on skin. Furthermore, as the pH value of the compounds of formula I may be neutral or approximately neutral, skin irritation problems following topical application may substantially be avoided.
DETAILED DESCRIPTION OF THE INVENTION
Preferred compounds of the invention are compounds of formula Ia
wherein
Q
1
and Q
2
are the same or different and independently represent a —(CHOH)— group; a —(CO)— group, or a —(CHSH)— group, or wherein Q
1
is a group
 wherein X is halogen;
R
1
represents an alkyl radical having 1 to 4 carbon atoms, an olefinic group having 2 to 4 carbon atoms, a (C
1
-C
6
)acyl group, a C
1
-C
7
cycloalkylcarbonyl group or a benzoyl group, R
1
being optionally substituted with one or more halogen atoms and/or hydroxy, alkoxy or azido groups;
and pharmaceutically acceptable salts and easily hydrolysable esters thereof.
Preferably Q
1
and Q
2
are selected from the group consisting of —(CO)— and —(CHOH)—. More preferred compounds of the invention are compounds of formula I or Ia wherein Q
1
and Q
2
both represent a
group; or one of Q
1
or Q
2
represents —(CO)—; A represents oxygen; R
1
represents a (C
1
-C
4
)alkyl group, optionally substituted with one or more substituents selected from the group consisting of azido, hydroxy, and halogen selected from fluoro, chloro and bromo, or R
1
represents an acyl group with 1 to 4 carbon atoms or a benzoyl group, both optionally substituted with one or more halogen atoms, preferably selected from the group consisting of fluoro and chloro. R
1
is preferably selected from the group consisting of ethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-azidoethyl, 2-hydroxyethyl, propyl, tert.-butyl, isopropyl, 1,3-difluoro-isopropyl, acetyl, propionyl, chloroacetyl and trifluoroacetyl, or R
1
is selected from the preferred group consisting of ethyl, 2,2,2-trichloroethyl, 2-azidoethyl, isopropyl, tert-butyl and acetyl. Also preferred are compounds of formula I and Ia wherein the bond between C-24 and C-25 is a double bond.
Examples of compounds of the invention which can all be prepared by the methods described below are:
17S,20S-Methanofusidic acid, Compound 101
24,25-Dihydro-17S,20S-methanofusidic acid, Compound 102
11-Dehydro-17S,20S-methanofusidic acid, Compound 103
3-Dehydro-17S,20S-methanofusidic acid, Compound 104
16-Deacetoxy-16&bgr;-propionyloxy-17S,20S-methanofusidic acid, Compound 105
16-Deacetoxy-16&bgr;-cyclohexylcarbonyloxy-17S,20S-methanofusidic acid, Compound 106
16-Deacetoxy-16&bgr;-(isopropionyloxy)-17S,20S-methanofusidic acid, Compound 107
16-Deacetoxy-16&bgr;-(4′-fluorobenzoyloxy)-17S,20S-methanofusidic acid, Compound 108
16-Deacetoxy-16&bgr;-furfuryloxy-17S,20S-methanofusidic acid, Compound 109
16-Deacetoxy-16&bgr;-ethoxy-17S,20S-methanofusidic acid, Compound 110
16-Deacetoxy-16&bgr;-(1′,1′,1′-trifluoroethoxy)-17S,20S-methanofusidic acid, Compound 111
16-Deacetoxy-16&bgr;-methoxymethyl-17S,20S-methanofusidic acid, Compound 112
3-Dehydro-3&bgr;-bromo-17S,20S-methanofusidic acid, Compound 113
3-Dehydro-3&bgr;-chloro-17S,20S-methanofusidic acid, Compound 114
and pharmaceutically acceptable salts and easily hydrolysable esters thereof.
In contrast to natural fusidic acid (1) wherein C-17 and C-20 are connected with a double bond, all compounds described herein and by formula I and Ia have a cyclopropane ring between C-17 and C-20. The configuration of the two asymmetric carbon atoms in question is 17(S) and 20(S).
The compounds of the invention can be used as such or in the form of salts or easily hydrolysable esters (as hereinafter defined). The salts of the compounds are especially the pharmaceutically acceptable salts, such as alkali metal salts and alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, as well as silver salts and salts with bases, such as ammonia or suitable non-toxic amines, such as lower alkylamines, for example triethylamine, hydroxy-lower alkylamines, for example 2-hydroxyethylamine, bis-

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